PB1797: ZNO NANOPARTICLES PROMOTES HUMAN ACUTE MYELOID LEUKEMIA (THP-1) CELL APOPTOSIS BASED ON MITOCHONDRIAL FISSION PATHWAY
Authors: X. Yin, Z. Li, L. Chunyi, W. yan, J. Wang, Y. Si, S. Cui, R. Xu
Journal: HemaSphere (2022)

Background: AML is a malignant tumor caused by changes in myeloid hematopoietic stem cells and abnormal changes in the proportion of primitive and immature myeloid cells. ZnO NPs have unique optical, chemical, electrical conductivity, antibacterial and anti-tumor properties, and are widely used in antibacterial, wound healing and tumor treatment. Mitochondria are a highly dynamic organelle that is important for many biological processes. At present, the effect of ZnO NPs on mitochondrial division and on human THP-1 cell apoptosis is still unclear. Aims: The present study aimed to elucidate the underlying mechanism of ZnO NPs induced apoptosis in acute myeloid leukemia (AML) cells by regulating mitochondrial division. Methods: The inhibitory effect of ZnO NPs on THP-1 cell proliferation was monitored by the CCK-8 method, and the THP-1 cells were incubated with different concentrations (i.e., 0, 10, 20, 40 μM) ZnO NPs for 24 h. The expression of mitochondrial division related factor Drp-1, apoptosis related factor Bcl-2, Bax mRNA and protein was detected by Q-PCR and WB, respectively. Moreover, the effects of ZnO NPs on the levels of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), apoptosis and ATP generation in leukemia cells were measured, and the effect of Drp-1 inhibitor Mdivi-1 and ZnO NPs on THP-1 cells was further detected. In addition, the relationship between Drp-1-mediated mitochondrial division and ZnO NPs-induced apoptosis in human leukemia cells was also explored. Results: The results showed that ZnO NPs could significantly inhibit cell proliferation and facilitate the apoptosis of THP-1 cells in a time- and dose-dependent manner. Meanwhile, the results also showed that ZnO NPs could significantly reduce the Δψm and ATP levels and induce the ROS production in THP-1 cells. The expression of Drp-1 and Bax at mRNA and protein levels was elevated whereas the mRNA and proteins levels of Bcl-2 were significantly decreased after the cells exposure to 10.0, 20.0, 40.0 μM of ZnO NPs for 24 h (all P<0.05). After intervention with different concentrations (0, 10.0, 20.0, and 40.0 μM, respectively) of Drp-1 inhibitor Mdivi-1, the Drp1 mRNA level was significantly reduced. Furthermore, the results also showed that the expression of Bax was significantly reduced, and the expression of Bcl-2 was increased after intervention with different concentrations of Drp-1 inhibitor Mdivi-1 (all P<0.05). Meanwhile, the apoptosis level of ThP-1 cells was significantly increased after exposure to ZnO NPs, whereas the apoptosis level was significantly reduced after the cell exposure to Drp-1 inhibitor Mdivi-1. Summary/Conclusion: The human AML cell survival rate decreased with the increment of ZnO NPs concentration and incubation time, accompanied by a dose-and time-dependent manner. ZnO NPs can reduce the cell Δψm and ATP levels, induce the ROS production in THP-1 cells, suggesting that the mitochondrial function was impaired or decreased. The levels of mitochondrial division and apoptosis of AML cells increased after exposure to ZnO NPs, indicating the activation of apoptosis pathway induced by ZnO NPs in human AML cells may be related to mitochondrial division. However, the apoptotic level was significantly reduced after intervention of Drp-1 inhibitor, confirming that ZnO NPs can induce the apoptosis of THP-1 cells by regulating mitochondrial division. Overall, ZnO NPs may provide a new basis and idea in treating human acute myeloid leukemia in clinical practice.